Kaposi'sarcoma (KS) is the most common cancer in AIDS patients, and is associated with infection of Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8). KS is a highly angiogenic vascular neoplasm primarily consisting of proliferating spindle endothelial cells with vast inflammatory infiltration. The long-term goal of our research program is to understand the molecular mechanism of KSHV-induced pathogenesis, providing a scientific basis for developing effective preventive and therapeutic approaches. Recent studies have shown that angiogenesis and inflammation are two central components in KS pathogenesis, and KSHV infection modulates these processes through a paracrine mechanism by inducing pro-angiogenic and inflammatory factors. The objective of this application is to define the mechanisms by which KSHV induces angiogenesis, and identify potential therapeutic targets for KSHV-induced malignancies. Our preliminary studies have shown that KSHV infection of human umbilical vein endothelial cells induces secretion of pro-angiogenic factors and represses secretion of angiogenesis inhibitors. Importantly, we have found that pro-angiogenic factors angiopoietin-2 (Ang-2), interleukin-6 (IL-6), and matrix metalloproteinase-1 (MMP-1) are highly induced by KSHV, and are also highly expressed in KS tumors. Significantly, we have shown that blocking Ang-2 alone with a neutralization antibody abolishes KSHV-induced paracrine-dependent angiogenesis in vivo. We hypothesize that KSHV infection induces angiogenesis through a paracrine mechanism by expressing specific viral gene products to modulate cellular angiogenic pathways, and as a result, targeting these angiogenic pathways can inhibit KSHV- induced tumorigenesis. To test this hypothesis, we will identify KSHV-regulated pro-angiogenic factors and angiogenesis inhibitors essential for KSHV-induced angiogenesis (aim I);determine the cellular pathways that mediate KSHV regulation of Ang-2, IL-6 and MMP-1 in latent infection (aim II);and identify viral genes that regulate the expression of Ang-2 (aim III). Finally, we will test the therapeutic applications of inhibiting KSHV-induced specific angiogenic pathways in tumor animal models (aim IV). The proposed project is innovative because it will use comprehensive multidisciplinary approaches to identify viral and cellular pathways, and pro-angiogenic factors/angiogenesis inhibitors that control KSHV-induced angiogenesis. These studies are significant because it will not only define the mechanism(s) of KSHV-induced angiogenesis but also identify potential therapeutic targets for KSHV-induced malignancies.

Public Health Relevance

Kaposi's sarcoma is a common malignancy in AIDS patients in US and worldwide inflicting morbidity and mortality to the society. This project will investigate the mechanism underlining the development of Kaposi's sarcoma, and identify potential targets for the prevention and treatment of this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA132637-06
Application #
8210868
Study Section
Special Emphasis Panel (ZRG1-AARR-C (04))
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2008-04-01
Project End
2014-01-31
Budget Start
2012-04-13
Budget End
2014-01-31
Support Year
6
Fiscal Year
2012
Total Cost
$329,252
Indirect Cost
$127,977
Name
University of Southern California
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Lee, Hye-Ra; Li, Fan; Choi, Un Yung et al. (2018) Deregulation of HDAC5 by Viral Interferon Regulatory Factor 3 Plays an Essential Role in Kaposi's Sarcoma-Associated Herpesvirus-Induced Lymphangiogenesis. MBio 9:
Liu, Hui; Wang, Huaizhi; Wei, Zhen et al. (2018) MeT-DB V2.0: elucidating context-specific functions of N6-methyl-adenosine methyltranscriptome. Nucleic Acids Res 46:D281-D287
Liang, Qiming; Wei, Dahai; Chung, Brian et al. (2018) Novel Role of vBcl2 in the Virion Assembly of Kaposi's Sarcoma-Associated Herpesvirus. J Virol 92:
Yan, Qin; Zhao, Runran; Shen, Chenyou et al. (2018) Upregulation of MicroRNA 711 Mediates HIV-1 Vpr Promotion of Kaposi's Sarcoma-Associated Herpesvirus Latency and Induction of Pro-proliferation and Pro-survival Cytokines by Targeting the Notch/NF-?B-Signaling Axis. J Virol 92:
Tan, Brandon; Liu, Hui; Zhang, Songyao et al. (2018) Viral and cellular N6-methyladenosine and N6,2'-O-dimethyladenosine epitranscriptomes in the KSHV life cycle. Nat Microbiol 3:108-120
Gruffaz, Marion; Zhou, Shenghua; Vasan, Karthik et al. (2018) Repurposing Cytarabine for Treating Primary Effusion Lymphoma by Targeting Kaposi's Sarcoma-Associated Herpesvirus Latent and Lytic Replications. MBio 9:
Cheng, Fan; Ramos da Silva, Suzane; Huang, I-Chueh et al. (2018) Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22. J Virol 92:
Gruffaz, Marion; Vasan, Karthik; Tan, Brandon et al. (2017) TLR4-Mediated Inflammation Promotes KSHV-Induced Cellular Transformation and Tumorigenesis by Activating the STAT3 Pathway. Cancer Res 77:7094-7108
Zhu, Ying; Li, Tingting; Ramos da Silva, Suzane et al. (2017) A Critical Role of Glutamine and Asparagine ?-Nitrogen in Nucleotide Biosynthesis in Cancer Cells Hijacked by an Oncogenic Virus. MBio 8:
Jeon, Hyungtaek; Yoo, Seung-Min; Choi, Hyo Sun et al. (2017) Extracellular vesicles from KSHV-infected endothelial cells activate the complement system. Oncotarget 8:99841-99860

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